This application concerns the further development, characterization and utilization of mouse models of non-small cell lung cancer. Given the prevalence and nearly universal lethal nature of lung cancer in humans, significant improvements in detection, treatment and prevention of this disease are desperately needed. In this application, this need will be addressed through the use of genetically-engineered mouse strains predisposed to lung cancer plus the development and deployment of a series of technical innovations to study them. This effort will involve the laboratories of Tyler Jacks (MIT), Matthew Meyerson and Todd Golub (DFCI, Whitehead Institute), and Jonathon Kurie (M.D. Anderson), in addition to a series of collaborators. Using strains developed it the current grant period, biochemical pathways regulated by the K-ras oncogene will be examined, including through chemical genetics approaches. Also, the stages of tumor progression, from of tumor initiation to metastasis, and the role of stromal elements in tumor development will be pursued. Additional studies will be performed to catalog the genomic and gene expression changes that accompany tumorigenesis in these models. Statistical methods will be developed to compare gene expression datasets from mouse and human lung cancer, as a means to interrogate the model but also as a way to focus attention of particular human genes of interest. Improved methods for early detection for lung cancer will be explored using serum proteomic screens and data from mouse models will be compared to human data obtained from similar screens. Pre-clinical screening of potential anti-cancer compounds will be performed using mouse lung tumor models, aided by improved methods for non-invasive imaging. Finally, new techniques for mouse model development will be developed, including methods to produce sequential gene alterations and a series of RNAi-based methods to evaluate candidate genes in lung cancer progression and treatment.